ML030 : PDE4A (cAMP-specific 3',5'-cyclic Phosphodiesterase 4A) Inhibitor
ML030
Target Name
cAMP-specific 3',5'-cyclic Phosphodiesterase 4A
Target Alias
PDE4A
Target Class
Phosphodiesterase
Mechanism of Action
Inhibitor of PDE4A
Biological / Disease Relevance
cAMP response element-binding protein pathway
In vitro activity
IC50 (PDE4A1A)Inactive Control
Available
Target Information
The cyclic response element-binding proteins (CREB) are a class of transcription factors that bind to selected cAMP response element (CRE) segments of DNA and catalyze the transcription of these genetic sequences. CREB has been implicated as an important regulator of long term memory, and pharmacological enhancement of the CREB signaling pathway in memory may provide an attractive strategy for development of memory enhancing drugs. The primary secondary messenger for initiation of CREB signaling is cAMP. cAMP mediates the actions of numerous protein kinases and is a key element in the regulation of cellular calcium transport. The control of intracellular cAMP and cGMP levels exists as a balance between cAMP and cGMP synthesis via the action of adenylyl cyclase (AC) and guanylyl cyclase, respectively, and degradation (hydrolysis) by phosphodiesterases (PDEs). The presence of these cyclic nucleotides has regulatory effects on protein kinase A (PKA) and protein kinase G (PKG), the guanine-nucleotide exchange factors (GEFs), and the cyclic-nucleotide gated (CNG) sodium and calcium channels. Small molecules modulators of PDEs (specifically PDE4) are likely to be strong regulators of CREB signaling.
Project Team
Properties
ML030
triazolothiadiazine, 5
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 412.5 g/mol | |||
| Molecular Formula | C20H20N4O4S | |||
| cLogP | 3.8 | |||
| PSA | 105 A^2 | |||
| Storage | ||||
| Solubility | ||||
| CAS Number | ||||
SMILES:
COC1=CC(C2=NN=C3N2N=C(C4=CC(OC)=C(OC)C=C4)CS3)=C(OC)C=C1
InChI:
InChI=1S/C20H20N4O4S/c1-25-13-6-8-16(26-2)14(10-13)19-21-22-20-24(19)23-15(11-29-20)12-5-7-17(27-3)18(9-12)28-4/h5-10H,11H2,1-4H3
InChIKey:
DZAUSKKPHXFGNN-UHFFFAOYSA-N
Activity
Summary activity statement /
ML030 (CID17757146, SID29217043) is found to potently and selectively inhibit PDE4A1A. The selectivity of these compound was assessed by testing it against a panel of 12 PDE enzymes isoforms. ML030 demonstrated nanomolar inhibitory potency against all three PDE4 isozymes (PDE4A, PDE4B and PDE4D) but ≥100-fold lower potency against the other the nine PDEs tested, including no activity against PDE7A and PDE7B, which are closely homologous to PDE4. Importantly, ML030 showed potent inhibition of the therapeutically important PDE4B isoform.
In vitro activity - Selectivity
Summary /
PDE isoform selectivity data for ML030. Selectivity assay indicated that ML030 is a more potent inhibitor of PDE4 than rolipram (1).